Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
  • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
  • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
  • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
  • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
  • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
  • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
  • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
  • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
  • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
  • A61K9/7061—Polyacrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/30—Oestrogens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2121/00—Preparations for use in therapy

Definitions

• This invention relates generally to transdermal drug delivery systems, and more particularly, to transdermal drug delivery systems for the delivery of estrogen
• a transdermal system for example, a patch comprising a pressure-sensitive adhesive containing a drug, as a means of delivering drug through the skin
• transdermal ding delivery systems designed for the delivery of specific drugs, such as estrogen
• transdeimal drug delivery systems that exhibit desired pharmacokinetic properties
• Transdermal delivery systems as dosage forms have been the subject of a vast number of patent applications over the last 25 years, yielding many patents but few commercial products in comparison 1 o those working in the field, the relatively small number of commercial products is not surprising
• regulatory, economic, and market hurdles play a role in limiting the number of products on the market
• a transdermal drug delivery system comp ⁇ sing a drug containing layer defining an active surface area and comp ⁇ sing a polymer mat ⁇ x comprising estradiol, wherein the system includes greater than 0 156 mg/cnf estradiol and achieves an estradiol flux that is greater than 0 01 mg/cm 2 /day, based on the active surtace area
• the polymer matrix comprises a polymer blend comprising an acrylic adhesive, a silicone adhesive, and soluble PVP
• the polymer matrix comprises about 2-25% by weight acrylic adhesive, about 45-70% by weight silicone adhesive, about 2-25% by weight soluble PVP, about 5-15% penetration enhancer, and about 0 1-10% by weight estradiol, all based on the total dry weight of the polymer mat ⁇ x
• the polymer matrix comprises about 20% by weight acrylic adhesive, about 56 9% by weight silicone adhesive, about 7 5% by weight soluble PVP,
• the polymer matrix comprises an amount of estradiol effective to deliver a therapeutically effective amount of estradiol over a pc ⁇ od of time selected from the group consisting of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at least 7 days
• the polymer matrix comp ⁇ ses an amount of estradiol effective to deliver an amount of estradiol selected from the group consisting of about 0 025, 0 0375, 0 05, 0 075 and 0 1 mg/day
• the polymer matrix has a coat weight of greater than about 10 mg/cm In some embodiments, the polymer matrix has a coat weight selected from the group consisting of about 12 5 and about 15 mg/ cm 2 [0009] In some embodiments the system has an active surface area that is about 60% of a size selected from the group consisting of 2 5, 3 75, 5 0, 7 5 and 10 0 cm" and is effective to deliver an amount of estradiol per day of about 0 025, 0 0375, 0 05, 0 075 and 0 1 mg/day, respectively
• a transdermal drug delivery system comprising a polymer mat ⁇ x comprising estradiol, wherein the system has an active surface area that is about 60% of a size selected from the group consisting of 2 5, 3 75, 5 0, 7 5 and 10 0 cm" and is effective to deliver an amount of estradiol per day of about 0 025, 0 0375, 0 05, 0 075 and 0 1 mg/day, respectively [0011]
• a method for administering estradiol comprising applying to the skin or mucosa of a subject in need thereof a transdermal drug delivery system as described herein, such as a transdermal drug delivery system comprising a drug-containing layer defining an active surface area and comprising a polymer mat ⁇ x comp ⁇ sing estradiol, wherein the system includes greater than 0 156 mg/cm 2 estradiol and achieves an estradiol flux that is greater than
• the system has an active surface area that is about 60% of a size selected from the group consisting of 2.5, 3.75, 5.0, 7.5 and 10.0 cm 2 .
• the polymer matrix comprises about 20% by weight acrylic adhesive, about 56.9% by weight silicone adhesive, about 7.5% by weight soluble PVP, about 6.0% by weight oleyl alcohol, about 8.0% by weight dipropylene glycol, and about 1 .6% by weight estradiol.
• the polymer matrix is applied to the support layer at a coat weight of greater than about 10 mg/cm 2 .
• the polymer matrix coat weight is selected from the group consisting of about 12.5 and about 15 mg/ cm 2 .
• Figure 1 illustrates the estradiol flux ( ⁇ g/cm /hr) over time (0-81 hours) from transdermal delivery systems according to the invention ( A & •), as compared to Vivelle-Dot® ( ⁇ ).
• transdermal delivery systems suffers from the problem of needing to balance many different competing factors to develop a commercial product that exhibits, for example both clinical efficacy and satisfactory wear properties while remaining acceptable to patients. For example, when selecting the size of a transdermal delivery system, it is necessary to balance factors that favor a smaller size (such as lower cost , better adhesive performance and improved aesthetics) against factors that favor a larger size (such as the target delivery rate (flux) and daily dose).
• the Vivelle-Dot® transdermal estradiol product (manufactured by N oven Pharmaceutcials Inc.) is available in five different active surface areas (2.5, 3.75, 5.0, 7.5 and 10.0 cm ) which each deliver different amounts of drug per day (0.025, 0 0375, 0 05, 0 075 and 0 1 mg/day, respectively)
• Each of the Vivelle-Dot® products include 0 156 mg/cm 2 estradiol
• the present invention provides transdermal drug delivery systems for the transdeimal deh ⁇ ery of estrogen that have a smaller active surface area than Vivelle-Dot® but achieve daily dosages that are about equal to or greater than the Vivelle-Dot® products
• the present invention includes transdermal drug delivery systems that achieve daily dosages that are about equal to a Vivelle-Dot® product, in a smaller sized system The ability to provide a smaller system without sacrificing daily dosage represents a significant advance
• the systems exhibit increased flux than other known estrogen devices (such as Vivelle-Dot®, manufactured by Noven Pharmaceutcials Inc ) and, therefore, exhibit increased drug delivery per unit area
• the systems exhibit a flux greater than the 0 01 mg/cm 2 /day exhibited by the Vivelle- Dot® products, such as a flux that is about 1 25 (including 1 125 to 1 375, such as
• the systems have a greater coat weight than other known estrogen devices
• the systems have a coat weight such that the amount of estradiol per unit area is greater than the 0 156 mg/cm 2 estradiol of the Vivelle-Dot® products, such as a coat weight that is about 1 25 (including 1 125 to 1 375, such as 1 25), about 1 33 (including 1 197 to 1 463, such as 1 33), about 1 5 (including 1 35 to 1 65, such as 1 5), about 1 67 (including 1 503 to 1 837, such as 1 67), about 1 75 (including 1 575 to 1 925, such as 1 75), about 2 (including 1 8 to 2 2, such as 2), about 3 (including 2 7 to 3 3, such as 3), about 4 (including 3 6 to 4 4, such as 4), or about 5 (including 4 5 to 5 5, such as 5) times the flux of the Vivelle-Dot® products
• the systems have a greater coat weight than other known estrogen devices
• the systems have a coat weight such that the amount
• the phrases "therapeutically effective amount” and “therapeutic level” mean that drug dosage or plasma concentration in a subject, respectively, that provides the specific pharmacological response for which the drug is administered in a subject in need of such treatment It is emphasized that a therapeutically effective amount or therapeutic level of a drug will not always be effective in treating the conditions/diseases described herein, even though such dosage is deemed to be a therapeutically effective amount by those of skill in the art
• exemplary dosages, drug delivery amounts, therapeutically effective amounts and therapeutic levels are provided below with reference to adult human subjects Those skilled in the art can adjust such amounts in accordance with standard practices as needed to treat a specific subject and/or condition/disease
• active surface area means the surface area of the drug- containing layer of the transdermal drug delivery system
• coat weight refers to the weight of the drug-containing layer per unit area of the active surface area of the transdermal drug delivery system
• estrogen includes estrogenic steroids such as estradiol (17-/3-estradiol), estradiol benzoate, estradiol 17/3-cypionate, estropipate, equilenin, equilin, est ⁇ ol, estrone, ethinyl estradiol, conjugated estrogens, este ⁇ fied estrogens, and mixtures thereof
• lux also called “permeation rate”
• permeation rate is defined as the absorption of a drug through skm or mucosal tissue, and is desc ⁇ bed by Fick's first law of diffusion
• J is the flux in g/cm 2 /sec
• D is the diffusion coefficient of the drug through the skin or mucosa in cm /sec
• dCm/dx is the concentration gradient of the drug across the skin or mucosa
• transdermal refers to delivery, administration or application of a drug by means of direct contact with skin or mucosa Such delivery, administration or application is also known as dermal, percutaneous, transmucosal and buccal.
• skin includes skin and mucosa, which includes oral, buccal, nasal, rectal and vaginal mucosa
• transdermal drug delivery system refers to a system (e g , a device) comprising a composition that releases estrogen upon application to the skin (or any other surface noted above)
• a transdermal drug delivery system may comprise a backing layer, a drug-containing layer, and a release liner layer
• the transdermal drug deliv ery system is a substantially non-aqueous, solid form, capable of conforming to the surface with which it comes into contact, and capable of maintaining such contact so as to facilitate topical application without adverse physiological response, and without being appreciably decomposed by aqueous contact during topical application to a subject
• transdermal drug delivery system comprises a drug-containing polymer matrix that comprises a pressure- sensitive adhesive or bioadhesive, and is adopted for direct application to a user's (e g , a subject's) skin
• a user's e g , a subject's
• polymer matrix refers to a polymer composition which contains one or more drugs
• the matrix comprises a pressuie- sensitive adhesive polymer or a bioadhesive polymer
• the mat ⁇ x does not comprise a pressure-sensitive adhesive or bioadhesiv e
• a polymer is an "adhesive" if it has the properties of an adhesive per se, or if it functions as an adhesive by the addition of tackifiers, plasticizers, crosslinking agents or other additives
• the polymer matrix comprises a pressure-sensitive adhesive polymer or a bioadhesive polymer, with estrogen dissolved or dispersed therein
• the polymer matrix also may comprise one or more of an> tackifiers, plasticizers, crosslinking agents or other additives described herein
• U S Patent 6,024,976 describes polymer blends that are useful in accordance with the transdermal systems described herein The entire contents
• pressure-sensitive adhesrve refers to a viscoelastic material which adheres instantaneously to most substrates with the application of very slight pressure and remains permanently tacky
• a polymer is a pressure-sensitive adhesive within the meaning of the term as used herein if it has the properties of a pressure-sensitive adhesive per se or functions as a pressure-sensitive adhesive by admixture with tackifiers, plasticizers or other additives
• pressure-sensitive adhesive also includes mixtures of different polymers and mixtures of polymers, such as polyisobutylenes (PIB), of different molecular weights, wherein each resultant mixture is a pressure-sensitive adhesive
• PIB polyisobutylenes
• the polymers of lower molecular weight in the mixture are not considered to be "tackifiers," said term being reserved for additives which differ other than in molecular weight from the polymers to which they are added
• the polymer matrix is a pressure-sensitive adhesive at room temperature and has other desirable characteristics for adhesives used in the transdermal drug delivery art Such characteristics include good adherence to skin, ability to be peeled or otherwise removed without substantial trauma to the skin, retention of tack with agmg, etc
• the polymer matrix has a glass transition temperature (T g ), measured using a differential scanning calorimeter, of between about -70 0 C and 0 0 C
• the te ⁇ n "rubber-based pressure-sensitive adhesive” refers to a viscoelastic mate ⁇ al which has the properties of a pressure-sensitive adhesive and which contains at least one natural or synthetic elastomeric polymer
• the transdermal drug delivery system includes one or more additional layers, such as one or more additional polymer matrix layers, or one or more adhesive lasers that adhere the transdermal drug delivery system to the user's skin
• the transdermal drug deliver ⁇ system is monolithic, meaning that it comprises a single polymer matrix layer comprising a pressure- sensitive adhesive or bioadhesive with drug dissolved or dispersed therein, and no rate-controlling membrane
• the transdermal drug delivery system may include a drug impermeable backing layer or film
• the backing layei is adjacent one face of the polymer matrix layei
• the backing layer protects the polymer matrix layer (and any other layers present) from the environment and prevents loss of the drug and/or release of other components to the environment during use
• Materials suitable for use as backing layers are well-known known in the art and can comprise films of polyester, polyethylene, vinyl acetate resins, ethyl ene/vmyl acetate copolymers, polyvinyl chloride, polyurethane, and the like, metal foils, non-woven fabric, cloth and commercially available laminates
• a typical backing material has a thickness in the range of 2 to 1000 micrometers
• the transdermal drug delivery system may include a release liner, typically located adjacent the opposite face of the system as compared to the backing layer When present, the release lmer is removed from the system prior to use to expose the polymer matrix layer and/or an adhesive layer prior to topical application
• a release liner typically located adjacent the opposite face of the system as compared to the backing layer
• Materials suitable for use as release liners include the commercially available products of Dow Corning Corporation designated Bio- Release® liner and Syl-off® 7610 and 3M's 1022 Scotch Pak
• a "monolithic" transdermal drug delivery system may include a backing layer and/or release liner
• the transdermal dug delivery system comp ⁇ ses a drug-containing polymer mat ⁇ x layer that comprises a pressure-sensitive adhesive blend comp ⁇ sing one or more of an acrylic polymer, a silicone polymer, and/or a soluble PVP, such as a pressure-sensitive adhesive blend comprising an acrylic polymer and a silicone polymer, an acrylic polymer and a soluble PVP, a silicone polymer and a soluble PVP, or an acrylic polymer, a silicone polymer, and a soluble PVP
• the term "acrylic polymer” is used here as in the art interchangeably with “polyacrylate,” “polyacrylic polymer,” and “acrylic adhesive "
• the acrylic-based polymers can be any of the homopolymers, copolymers, terpolymers, and the like of various acrylic acids or esters In some embodiments, the acrylic-based polymers are adhesive polymers. In other embodiments, the acrylic-based polymers function as an adhesive by the addition of tackifiers, plasticizers, crosslmkmg agents or other additives.
• the term "acrylic polymer” may include a combination of any one or more acrylic polymers as described herein, such as one or more homopolymers, copolymers, terpolymers and/or multipolymers.
• the acrylic polymer can include homopolymers, and/or can include copolymers, terpolymers and/or multipolymers.
• the acrylic polymer can be any of the homopolymers. copolymers, terpolymers, and the like of various acrylic acids.
• the acrylic polymer constitutes from about 2% to about 95% by weight of the polymer content of the polymer matrix, including about 3% to about 90% and about 5% to about 85%, such as 2% to 95%, 3% to 90% and 5% to 85%
• the amount and type of acrylic polymer is dependent on the type and amount of estrogen used
• Acrylic polymers useful in practicing the invention include polymers of one or more monomers of acrylic acids and other copolymerizable monomers.
• the acrylic polymers also include copolymers of alkyl acrylates and/or methacrylates and/or copolymerizable secondary monomers or monomers with functional groups Combinations of acrylic-based polymers based on their functional groups is also contemplated.
• Acrylic-based polymers having functional groups include copolymers and terpolymers which contain, in addition to nonfunctional monomer units, further monomer units having free functional groups The monomers can be monofunctional or polyfunetional. By varying the amount of each type of monomer added, the cohesive properties of the resulting acrylic polymer can be changed as is known in the art.
• the acrylic polymer is composed of at least 50% by weight of an acrylate or alkyl acrylate monomer, from 0 to 20% of a functional monomer copolymerizable with the acrylate, and from 0 to 40% of other monomers.
• Acrylate monomers which can be used include any one or more of acrylic acid and methacrylic acid and alkyl acrylic or methacrylic esters such as methyl acrylate, ethyl acrylate, propyl acrylate, amyl acrylate, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, heptyl acrylate, octyl acrylate, nonyl acrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylatc, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl mcthacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl
• Non-functional acrylic-based polymers can include any one or more acrylic based polymer(s) having no or substantially no free functional groups.
• Functional monomers, copolymerizable with the above alkyl acrylates or methacrylates, which can be used include any one or more of acrylic acid, methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrilc, dimcthylaminoethyl acrylate, dimethylaminoethyl methacrylatc, tcrt-butylaminoethyl acrylate, tert-butylaminoethyl mcthacrylate, methoxyethyl acrylate and methoxyethyl methacrylate.
• “functional monomers or groups” are monomer units typically in acrylic-based polymers which have reactive chemical groups which modify the acrylic-based polymers directly or which provide sites for further reactions.
• Examples of functional groups include carboxyl, epoxy, hydroxyl, sulfoxyl, and amino groups.
• Acrylic-based polymers having functional groups contain, in addition to the nonfunctional monomer units described above, further monomer units having free functional groups.
• the monomers can be monofunctional or polyfunctional.
• Typical functional groups include carboxyl groups, hydroxy groups, amino groups, amido groups, epoxy groups, etc.
• Typical carboxyl functional monomers include acrylic acid, methacrylic acid, itaconic acid, maleic acid, and crotonic acid.
• Typical hydroxy functional monomers include 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, hydroxymethyl acrylate, hydroxymethyl methacrylate, hydroxyethyl acrylate, hydroxyethyl methacrylate, hydroxypropyl acrylate, hydroxypropyl methacrylate, hydroxybutyl acrylate, hydroxybutyl methacrylate, hydroxyamyl acrylate, hydroxyamyl mcthacrylate, hydroxyhexyl acrylate, hydroxyhexyl mcthacrylate.
• the any one or more acrylic polymer does not include such functional groups.
• Suitable acrylic polymers also include pressure-sensitive adhesives which are commercially available, such as any one or more of the acrylic-based adhesives sold under the trademarks DURO-TAK® by National Starch and Chemical Corporation, Bridgewater, N.J. (such as DURO-TAKCR) 87-2287, -4098, -2852, -2196, -2296, -2194, -2516, -2070, -2353, -2154, -2510, -9085, -9088 and 73-9301).
• Other suitable acrylic adhesives include those sold under the trademark EUDRAGIT® by Roehm Pharma GmbH, Darmstadt, Germany, those sold by Cytec Surface Specialties, St.
• GELV A® Multipolymer Solution such as GELVA® 2480, 788. 737, 263, 1430, 1753, 1 151 , 2450, 2495, 3067, 3071 , 3087 and 3235.
• hydroxy functional adhesives with a reactive functional OH group in the polymeric chain can be used.
• Non-limiting commercial examples of this type of adhesives include both GELVA® 737, 788. and 1 151. and DURO-TAK® 87-2287, -4287, -2510 and -2516.
• any one or more acrylic polymers may be used.
• silicone-based polymer is used interchangeably with the terms siloxane, polysiloxane, and silicones as used herein and as known in the art.
• a suitable silicone-based polymer may also be a pressure-sensitive adhesive.
• the silicone-based polymer is an adhesive polymer.
• the silicone-based polymer functions as an adhesive by the addition of tackifiers, plasticizers, crosslinking agents, or other additives. Any silicon polymer described herein, or any combination of two or more, may be used.
• Suitable polysiloxanes include silicone pressure-sensitive adhesives which are based on two major components: (i) a polymer or gum and (ii) a tackifying resin.
• a polysiloxane adhesive can be prepared by cross-linking a gum, typically a high molecular weight polydiorganosiloxane, with a resin, to produce a three-dimensional silicate structure, via a condensation reaction in an appropriate organic, volatilve solvent, such as ethyl acetate or heptane
• the ratio of resin to polymer can be adjusted in order to modify the physical properties of polysiloxane adhesives Sobieski, et al , "Silicone Pressure Sensitive Adhesives," Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed , pp 508-517 (D Satas, ed ), Van Nostrand Remhold, New York (1989)
• sihcone-based polymers are adhesives (e g , capable of sticking to the site of topical application), including pressure-sensitive ddhesives
• sihcone-based polymers having reduced silanol concentrations include sihcone-based adhesives (and capped polysiloxane adhesives) such as those desc ⁇ bed in U S Pat No Re 35,474 and U S No 6,337,086, which are incorporated herein by reference in their entireties, and which are commercially available from Dow Corning Corporation (Dow Corning Corporation, Medical Products, Midland, Michigan) as BIO-PSA® 7-4100, -4200 and -4300 product series, and non-sensiti7ing, pressure- sensitive adhesives produced with compatible organic volatile solvents (such as ethyl acetate or heptane) and available commercially under their BIO-PSA® 7-4400 series -4500 series and -4600 series
• silicone pressure-sensitive adhesives which are useful in the polymer matrices and compositions and methods desc ⁇ bed herein are mentioned in the following U S Pat Nos 4,591 ,622, 4,584,355, 4,585,836, and 4,655,767, which are all expressly incorporated by reference herein in their entireties It should also be understood that silicone fluids are also contemplated for use in the polymer matrices and methods desc ⁇ bed herein
• the polysiloxane constitutes from about 9% to about 97% of the polymer content of the polymer mat ⁇ x, including about 8% to about 97% and about 14% to about 94%, such as 9% to 97%, 8% to 97%, and 14% to 94% Soluble PVP
• the polymer matrix includes soluble PVP
• Soluble PVP has been found to be highly effective in preventing crystallization of drugs, such as estradiol, in adhesive-type transdermal drug delivery system Soluble PVP also may modulate the transdermal permeation rate of the drug Any soluble PVP described herein, or any combination of two or more, may be used
• the term "PVP or "polyvinylpyrrolidone” refers to a polymer, typically either a homopolymer or copolymer, containing N-vinylpyrrolidone as the monomeric unit
• Typical PVP polymers are homopolymeric PVPs and the copolymer vinyl acetate vinylpyrrohdonc
• the homopolymeric PVPs arc known to the pharmaceutical industry under a vanety ot designations including Povidone, Polyvidone, Polyvidonum, Polyvidonum soluble, and Poly(l-vinyl-2-pyrrohdone)
• the polymer matrix comprises a soluble PVP with a rubber-based pressure-sensitive adhesive and a polyacrylate polymer, such as a blend of an acrylic polymer, a polysiloxane and a soluble PVP In some embodiments, the blend is chosen to affect the rate of drug delivery.
• a plurality of polymers including a soluble polyvinylpyrrolidone which may have different solubility parameters for the drug and which may be immiscible with each other, may be selected to adjust the solubility of the drug in the polymer matrix, thereby controlling the maximum concentration oi the drug in the system, and modulating drug delivery through the dermis
• the amount of each polymer component such as the amount of acrylic- based polymer and si Ii cone-based polymer can be adjusted so as to modify the saturation concentration of the drug in the polymer mat ⁇ x in order to affect the rate of delivery of the drug from the system and through the skin
• the acrylic-based polymer and silicone-based polymer are used in a weight ratio of from about 2 98 to about 96 4, including about 2 98 to about 90 10 and 2 98 to about 86 14, such as 2 98 to 96 4, 2 98 to 90 10 and 2 98 to 86 14
• the concentration by weight of the estrogen in the transdermal drug delivery system is typically about 0 1 to about 50 %, including about 0 1 to about 40 % and about 0 3 to about 30 %, such as 0 1 to 50 %, 0 1 to 40 % and 0 3 to 30 %, all based on the total weight of the polymer matrix
• the estrogen is estradiol, and is present at an amount of from about 0 1 to 10%, including from about 0 1 to about 5 %, such as from 0 1 to 10% and 0 1 to 5%, all based on the total weight of the polymer matrix
• the pressure-sensitive adhesive composition can be formulated to maintain acceptable shear, tack, and peel adhesive properties
• the transdermal drug delivery system may comprise any one or more of the following components
• the polymer matrix comprises one or more penetration enhancers
• a “penetration enhancer” is an agent known to accelerate the delivery of the drug through the skin
• These agents also have been referred to as accelerants, adjuvants, and sorption promoters, and are collectively referred to herein as “enhancers "
• This class of agents includes those with diverse mechanisms of action, including those which have the function of improving percutaneous absorption, for example, by changing the ability of the stratum corneum to retain moisture, softening the skin, improving the skin's permeability, acting as penetration assistants or hair- follicle openers or changing the state of the skm including the boundary layer
• Illustrative penetration enhancers include but are not limited to polyhyd ⁇ c alcohols such as dipropylene glycol, propylene glycol, and polyethylene glycol, oils such as olive oil, squalene, and lanolin, fatty ethers such as cetyl ether and oleyl ether, fatty acid esters
• Other agents include oleic and lmoleic acids, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linolcate. propyl oleate, and isopropyl palmitate
• the penetration enhancer is oleyl alcohol
• the penetration enhancer is a glycol, such as dipropylene glycol, propylene glycol, butylene glycol or polyethylene glycol
• the penetration enhancer comprises a mixture of at least two penetration enhancers
• a penetration enhancer may comp ⁇ se oleyl alcohol and one or more polyhyd ⁇ c alcohols, such as glycerine, dipropylene glycol, butylene glycol, propylene glycol
• the penetration enhancer may include oleyl alcohol and dipropylene glycol
• a penetration enhancer is used m an amount up to about 30% by dry weight of the polymer matrix (including up to 27% to 33%, such as up to 30%) up to about 20% (including up to 18% to 22%, such as up to 20%), up to about 10% (including up to 9% to 1 1 %, such as up to 10% by weight), or up to about 5% (including up to 4 5 to 5 5%, such as 5%) by weight, based on the dry weight of the polymer mat ⁇ x
• a penetration enhancer is used in an amount of from about 5% to about 15%, including from 4 5 to 16 5%, such as from 5% to 15%
• the penetration enhancer comp ⁇ ses a mixture of oleyl alcohol and dipropylene glycol which together amount to about 14 %, including 12 6% to 15 4%, such as 14% by weight ol the polymer matrix
• the polymer matrix may further comp ⁇ se various thickeners, fillers, and other additives or components known for
• the transdermal drug delivery system comprises a smaller amount of estradiol than a Vivelle-Dot® product, but achieves comparable drug delivery
• a transdermal drug delivery system according to the invention may contain about 1 44 mg (including 1 296 to 1 584 mg, such as 1 44 mg), or about 1 2 mg (including 1 08 to 1 32 mg, such as 1 2 mg) of estradiol in a 6 cm 2 device, and achieve drug delivery comparable to a Vivelle-Dot® product that contains about 1 56 mg estradiol in a 10 cm 2 device
• the system comprises a polymer matrix comprising an amount of acryhc-bascd polymer of about 1 to about 70% by weight, including about 2 to about 25 % by weight, based on the dry weight of the polymer matrix, such as 2-25 % by weight acrylic-based polymer
• the system comprises a polymer matrix comprising an amount of silicone polymer of about 5 to about 70% by weight, including about 45 to about 70% by weight, based on the dry weight of the polymer matrix, such as 45-70 % by weight silicone polymer
• the system comprises a polymer matrix comprising an amount of soluble PVP of about 1 to about 30% by weight, including about 2 to about 25 % by weight, based on the dry weight of the polymer matrix, such as 2-25 % by weight soluble PVP
• the system comprises a polymer matrix comprising an amount of oleyl alcohol of about 1 to about 10% by weight, including about 4 to about 8% by weight, based on the dry weight of the polymer mat ⁇ x, such as 4-8% by weight oleyl alcohol
• the system comprises a polymer matrix comprising an amount of dipropylene glycol of about 1 to about 10% by weight, including about 5 to about 10% by weight, based on the dry weight of the polymer mat ⁇ x, such as 5- 10% by weight dipropylene glycol
• the polymer matrix comprises about 2-25% by weight acrylic adhesive, about 45-70% by weight silicone adhesive, about 2-25% by weight soluble PVP, about 5-1 5% penetration enhancer, and about 0.1 -10% by weight estradiol, all based on the total dry weight of the polymer matrix.
• the polymer matrix comprises about 20% (including 18% to 22%, such as 20%) by weight acrylic adhesive, about 56 9% (including 51 21 % to 62 59%, such as 56.9%) by weight silicone adhesive, about 7.5 % (including 6.75% to 8 25%, such as 7.5%) by weight soluble PVP; about 6.0% (including 5.4% to 6.6%, such as 6.0%) by weight oleyl alcohol; about 8.0% (including 7 2% to 8.8%. such as 8.0%) by weight dipropylene glycol; and about 1.6% (including 1.44% to 1.76%, such as 1.6%) by weight estradiol.
• the acrylic adhesive and silicone adhesive are present in a ratio of from about 1 '2 up to less than about 1 :7, such as up to about 1 :6, based on the weight of the acrylic and silicone adhesives
• the acrylic adhesive and silicone adhesive are present in a ratio of about 1 2, 1 3, 1 "4, 1 :5 or 1 6, based on the weight of the acrylic and silicone adhesives
• the acrylic adhesive and silicone adhesive are present in a ratio of 1 :2.8, based on the weight of the acrylic and silicone adhesives
• the polymer matrix can serve as an adhesive portion of the system (e.g., a reservoir device), or can serve as one or more layers of a multi-layer system
• a polymer matrix comprising a pressure-sensitive adhesive or bioadhesive with drug dissolved or dispersed therein can constitute a monolith
• the polymer matrix does not comprise an adhesive, but instead, for example, comprises a polymeric drug reservoir, it can be used in combination with one or more adhesive layers, or with a surrounding adhesive portion, as is well known to those skilled in the art.
• the system consists essentially of the polymer matrix layer.
• consists essentially of the polymer matrix layer means that the system does not contain any other layers that affect drug delivery, such as an additional rate- controlling polymer layer, rate-controlling membrane, or drug reservoir layer It will be understood, however, that the system that consists essentially of the polymer matrix layer may comprise a backing layer and/or release liner.
• the systems have a greater flux than other known estrogen devices (such as Vivelle-Dot®, manufactured by Noven Pharmaceutcials Inc.), and, therefore, exhibit increased drug delivery per unit area of the active surface area.
• other known estrogen devices such as Vivelle-Dot®, manufactured by Noven Pharmaceutcials Inc.
• the systems exhibit a flux greater than the 0.01 mg/c ⁇ T/day exhibited by the Vivelle-Dot® products, such as a flux that is about such as a flux that is about 1.25 (including 1.125 to 1.375, such as 1.25), about 1.33 (including 1.197 to 1.463, such as 1.33), about 1.5 (including 1.35 to 1.65, such as 1.5), about 1.67 (including 1.503 to 1.837, such as 1.67), about 1.75 (including 1.575 to 1.925, such as 1.75), about 2 (including 1.8 to 2.2, such as 2), about 3 (including 2.7 to 3.3, such as 3), about 4 (including 3.6 to 4.4, such as 4), or about 5 (including 4.5 to 5.5, such as 5) times the flux of the Vivelle-Dot® products.
• the systems exhibit a flux that is about 1.67 times (including 1.503 to 1.837 times, such as 1.67 times) the flux of the Vivelle-Dot® products, e.g., a flux that is about 0.0167 mg/cm 2 /day (including 0.01503 to 0.01837 mg/cm 2 /day, such as 0.0167 mg/cm 2 /day).
• the systems have a greater coat weight than other known estrogen devices.
• the systems have a coat weight such that the amount of estradiol per unit area of the active surface area is greater than the 0.156 mg/cm 2 estradiol of the Vivelle-Dot® products, such as a coat weight that is about 1.25 (including 1.125 to 1.375, such as 1.25), about 1.33 (including 1 .197 to 1.463, such as 1.33), about 1.5 (including 1.35 to 1.65, such as 1.5), about 1.67 (including 1.503 to 1.837, such as 1.67), about 1.75 (including 1.575 to 1.925, such as 1.75), about 2 (including 1.8 to 2.2, such as 2), or about 3 (including 2.7 to 3.3, such as 3), times the coat weight of the Vivelle-Dot® products, or greater.
• the systems have a coat weight that is about 1.25 times the coat weight of the Vivelle-Dot® products, e.g., a coat weight of about 12.5 mg/cm 2 (including 1 1.25 to 13.75 mg/cm 2 , such as 12.5 mg/cm 2 ). In other specific embodiments, the systems have a coat weight that is about 1.5 times the coat weight of the Vivelle-Dot® products, e.g., a coat weight of about 15 mg/cm" (including 13.5 to 16.5 mg/cm 2 , such as 15 mg/cm 2 ). [0077]
• the system may be of any shape or size suitable for transdermal application.
• the systems arc smaller than the Vivelle-Dot® products, but achieve comparable daily dosages.
• the systems may have an active surface area of 0.9, 0.8, 0.7, 0.75, 0.66, 0.6, 0.5, 0.4, 0.33, 0.3, 0.25, 0.2, or 0.1 times the active surface area of a Vivelle-Dot® product.
• the system has an active surface area that is about 60% (including 54% to 66%, such as 60%) the size of a Vivelle-Dot® product, such as about 60% (including 54% to 66%, such as 60%) of 2.5, 3.75, 5.0, 7.5 or 10.0 cm 2 , and delivers a daily dosage of estradiol comparable to that of the corresponding Vivelle-Dot® product.
• the system has an active surface area of about 6 cm " (including 5.4 to 6.6 cm 2 , such as 6 cm 2 ) and delivers a daily dosage of estradiol comparable to that of the 10 cm 2 Vivelle-Dot® product, e.g., about 0.1 mg/day (including 0.09 to 1.1 mg/day, such as 1 mg/day).
• the polymer matrices described herein may be prepared by methods known in the art.
• the polymer matrices can be formed into systems by methods known in the art.
• the polymer matrix material can be applied to a backing layer and release liner by methods known in the art, and formed into sizes and shapes suitable for use.
• the polymer matrix may be brought into contact with a support layer, such a releaser liner layer or backing layer, in any manner known to those of skill in the art.
• a support layer such as a releaser liner layer or backing layer.
• Such techniques include calender coating, hot melt coating, solution coating, etc.
• a polymer matrix can be prepared by blending the components of the polymer matrix, applying the matrix material to a support layer such as a backing layer or release liner, and removing any remaining solvents.
• the estrogen can be added at any stage. In one embodiment, all polymer matrix components, including estrogen, arc blended together. In another embodiment, the polymer matrix components other than estrogen are blended together, and then the estrogen is dissolved or dispersed therein. The order of steps, amount of ingredients, and the amount and time of agitation or mixing can be determined and optimized by the skilled practitioner.
• An exemplary general method illustrated in the context of a specific embodiment comprising an acrylic polymer, polysiloxane and soluble PVP, is as follows
• Aprop ⁇ ate amounts of soluble PVP, sohent(s), enhancer(s), and organic sol ⁇ ent(s) are combined and thoroughly mixed together in a vessel
• Estrogen is then added to the mixture and agitation is earned out until the drug is uniformly mixed in
• Aprop ⁇ ate amounts of polysiloxane and acrylic polymer are then added to the drug mixture, and thoroughly mixed.
• T he formulation is then transferred to a coating operation where it is coated onto a protective release liner at a controlled specified thickness
• the coated product is then passed through an oven in order to drive off all volatile processing solvents
• the dried product on the release lmer is then joined to the backing material and wound into rolls for storage
• a method of effecting transdermal drug delivery of estrogen, such as estradiol by applying a system as described herein to the skin or mucosa of a subject in need thereof.
• the system composes estradiol, and the system is applied over a period of at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, or at least about 7 days, such as for 1 , 2, 3, 4, 5, 6 or 7 days
• the method is effective to achieve therapeutic levels of estrogen in the subject during the application period
• a typical dosage ranges from at least about 0 025 mg to at least about 0 1 mg of estradiol per day, such as from about 0 025 mg to about 0 1 mg of estradiol per day (including 0 0225 to 0 1 1 mg/day, such as 0 025 to 0 1 mg/day), such as about 0 025 (
• a polymer matrix with the following composition is prepared' Acrylic Adhesive 20%
• the polymer matrix is applied to a release liner at a coat weight of 12.5 (•) or 15 (A) mg/cm .

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